This invention relates to new formulations comprising coenzyme Q.sub.10 (CoQ.sub.10) in fat emulsions for use in clinical medicine. The fat emulsions used are those commonly administered intravenously to patients in clinical practice. Based on pharrmacokinetic data from healthy human subjects orally administered with CoQ.sub.10 (2,3-dimethoxy-5-methyl-6-decaprenyl benzoquinone), there is very slow absorption of CoQ.sub.10 as monitored, for example, by blood plasma levels. There is a lag time of about one hour before an increase in the plasma level of COQ.sub.10 is detected. Subsequently there was a maximum increase in the plasma level of CoQ.sub.10 after about 5 to 6 hours, which was relatively stable until up to about 24 hours when a second peak of plasma CoQ.sub.10 was measured. This slow absorption and the second maximum plasma level may relate to the insolubility of CoQ.sub.10 in aqueous media. The extreme lipophilicity of CoQ.sub.10 also may explain why as much as 62% of an orally administered dose has been recovered from the feces during a study period of 10 days. If feces were analyzed over a longer period, an even higher level of excretion of unchanged CoQ.sub.10 would be expected. The overall absorption of orally administered CoQ.sub.10 is expected to be in the range of 10-20% (Lucker et al., Biomedical and Clinical Aspects of Coenzyme Q. V 4; K. Folkers and Y. Yamamura, eds., Elsevier/North-Holland Biomedical Press, Amsterdam, 143-151, (1984)).
Sunamori et al. investigated the clinical application of CoQ.sub.10 to patients having coronary artery by-pass graft surgery (Biomedical and Clinical Aspects of Coenzyme Q. V 4, K. Folkers and Y. Yamamura, eds., Elsevier/North-Holland Biomedical Press, Amsterdam, 333-342 (1984)). Cardioplegia does not provide complete myocardial protection from ischemia, and a certain amount of perioperative myocardial infarction is inevitable, despite the generally low incidence of infarction associated with coronary artery bypass surgery. Sunamori et al. endeavored to determine whether the administration of CoQ.sub.10 would protect cardiac function in clinical coronary artery revascularization. They reported that the oral administration of CoQ.sub.10 failed to allow satisfactory tissue concentrations of CoQ.sub.10 under medically acceptable conditions for such surgery.
Approximately 40% of all drugs administered to patients in hospitals are given in the form of injections. Intravenous formulations now have a major role as vehicles for drugs. Intravenous formulations are finding a greater use in the administration of drugs, because of dependability, accuracy, convenience, avoidance of the gastric irritation potential of orally administered drugs, and the importance of continuous as well as intermittent drug therapy. Techniques for providing intravenous administrations have improved steadily in the last decade, and the use of such intravenous formulations has been anually increasing at the rate of about 40% (Remington's Pharmaceutical Sciences, 16th Ed., A. Osol, Ed., Mack, Easton, Pa., (1980), pp. 1488-1497).
Coenzyme Q.sub.10, being highly hydrophobic, is essentially insoluble in aqueous solutions. For CoQ.sub.10 to be parenterally administered, it must be contained in a stable formulation compatible with, for example, intravenous injection. One approach to prepare an intravenous formulation of coenzyme Q.sub.10 in an aqueous medium requires the inclusion of one or more surfactants and other entities which would allow the creation of a dispersion of particles of coenzyme Q.sub.10 in an aqueous medium. There are many difficulties associated with this approach. A prominent difficulty is related to the fact that CoQ.sub.10 is a solid at temperatures below about 50.degree. C. The dispersion of solid particles of CoQ.sub.10 in an aqueous medium involves difficulties in the preparation of a safe formulation with a stability up to about two years for clinical application. Such solid particle dispersions have been explored, but on standing, particles containing CoQ.sub.10 fall to the bottom of the container, and redispersion by stirring or shaking definitely does not meet the requirements for medical use. Successful formulations should have a stability of up to about two about years to become established for clinical use. The second prominent difficulty is having a formulation which, on intravenous administration, does not lead to particle separation or precipitation within the blood stream. Such a separation would be detrimental to blood flow and potentially be life-threatening.
It is unsafe and improper for pharmacists to make experimental formulations of CoQ.sub.10 of unproven quality and to provide such formulations to physicians for intravenous administration within days or a week or more.
Others have attempted to produce fatty emulsions of CoQ.sub.10. Yamaguchi et al. (J. Pharm. Pharmacol., (1984), 36:768-769) describe a fat emulsion of coenzyme Q.sub.10 (100 .mu.g(microgram)/ml), phospholipid, glycerol, soybean oil and water.
An Eisai Co. Ltd. reference (Chem. Abstracts, 100:367, No. 100:145017d) describes an injectable emulsion containing CoQ.sub.10 (ubidecarenone, 1 mg/ml), lecithin, ethanol, MACROGOL 400, sorbitol and water. European Patent Application Publication No. 0132821 described aqueous solutions comprising lipid-soluble substances such as coenzyme Q.sub.10 (preferably between 1 mg/ml and 10 mg/ml), hydrogenated lecithin and neutral amino acids.
U.S. Pat. No. 4,068,003 (Miyata) described an injectable emulsion containing coenzyme Q.sub.10 (10 mg/ml), detergemt Nikkol HCO-60, sesame oil, sodium chloride, propylene glycol and phosphate buffer.
U.S. Pat. No. 4,156,718 (Bliznakov) describes a treatment for reversal of immunological senescance involving administration of CoQ.sub.10. Oral administration of CoQ.sub.10 was preferred for humans and intravenous for lower animals. An emulsion comprising CoQ.sub.10 (125 .mu.g/ml, 5% glucose solution and detergent 0.4% Tween 20 (polyoxyethylene sorbitol monolaureate)).
No CoQ.sub.10 emulsion has been heretofore produced which is free of additions such as detergents or surfactants and having levels of CoQ.sub.10 sufficiently high to be clinically effective yet low enough to avoid potential toxic effects of intravenous CoQ.sub.10 excess.